This application is a continuation of PCT application PCT/FR99/01811, filed Jul. 23, 1999, and published in French as WO 00/07568 on Feb. 17, 2000. PCT/FR99/01811 claimed the priority of French application FR98/10091, filed Aug. 3, 1998. The entire disclosures of both are incorporated herein by reference.
The invention relates to a process for manufacturing coated particles of xcex3-aminobutyric acid (GABA) analogue containing less than 0.5% of lactam by weight relative to the weight of GABA analogue.
The invention also relates to the coated particles which can be obtained by the said process, as well as to any pharmaceutical form using the said coated particles.
In the description hereinbelow and in the claims, the invention is described more particularly in relation to the xcex3-aminobutyric acid analogues chosen from the group comprising gabapentin and pregabalin. However, as already stated, the process applies to any xcex3-aminobutyric acid analogue which can produce lactam molecules as degradation product.
Gabapentin, also known as 1-aminomethylcyclohexaneacetic acid, is a xcex3-aminobutyric acid (GABA) analogue. It has anti-convulsant properties and is used in the treatment of epilepsy. This well-known molecule is described in particular in documents U.S. Pat. No. 4,024,175 and U.S. Pat. No. 4,087,544.
From the point of view of pharmacokinetics, it is essential for the concentration of gabapentin in the plasma to reach its peak in 2 to 3 hours.
This is one of the reasons why gabapentin is currently sold in France in the form of gel-capsules filled with a mixture of powder consisting of gabapentin, hydrated lactose, corn starch and talc. The gel-capsules contain 100 mg, 300 mg or 400 mg doses of active principle and are sold under the trade name NEURONTIN(copyright) by Parke-Davis.
Although gel-capsules allow the satisfactory concentration of gabapentin in the plasma to be obtained, they are, however, unsuitable for pediatric use.
To solve this problem, attempts have been made to present gabapentin in the form of an aqueous solution.
However, the document Pharmaceutical Research, Volume 9, Number 5, 1992, demonstrates:
on the one hand, that gabapentin is liable to be degraded in aqueous solution to give, by intramolecular cyclization, a lactam-type degradation product, the content of which should not exceed 0.5% by weight relative to the weight of the active principle for any pharmaceutical form, irrespective of the dosage;
and, on the other hand, that gabapentin has a sufficiently bitter taste for it to be essential to mask its taste.
To solve the problem of masking the taste, document EP-A-0,458,751 proposed presenting gabapentin in the form of particles coated with a hydrophilic first layer of a water-insoluble polymer and a hydrophobic second layer. Even though satisfactory masking of the taste is obtained, the process of coating the first layer requires the presence of water, such that an intramolecular cyclization of gabapentin can be expected, leading to the formation of lactam inside the finished product itself.
Pregabalin is also a xcex3-aminobutyric acid analogue which is known as an anti-epileptic agent and is more particularly described in document WO 98/58641 for its application as an anti-inflammatory agent. The Applicant has observed that pregabalin displayed a phenomenon identical to that of gabapentin as regards its degradation in aqueous solution into lactam molecules. In addition, just like gabapentin, pregabalin must reach a maximum concentration in the plasma in 2 to 3 hours. Finally, this molecule also has a bitter taste, making it difficult to use in its native form in a pharmaceutical formulation.
The first problem which the invention proposes to solve is to provide a pharmaceutical form of a GABA analogue, whose lactam content is less than 0.5% by weight relative to the weight of GABA analogue.
The second problem which the invention proposes to solve is to provide a pharmaceutical form of a GABA analogue which can be used in paediatrics.
The third problem which the invention proposes to solve is to provide a pharmaceutical form of a GABA analogue in which the bitter taste of the said analogue is masked, while at the same time giving a maximum concentration in the plasma in 2 to 3 hours.
To do this, the invention proposes a process for manufacturing coated particles of a xcex3-aminobutyric acid analogue whose lactam content by weight relative to the weight of GABA analogue is less than 0.5%.
This process is characterized in that a coating solution comprising at least one polymer in at least one organic solvent is sprayed on to the said particles of xcex3-aminobutyric acid analogue.
In a first embodiment, the xcex3-aminobutyric acid analogue is gabapentin.
In another embodiment of the invention, the xcex3-aminobutyric acid analogue is pregabalin.
It has been found, entirely surprisingly, that the fact of coating the gabapentin or the pregabalin particles with a polymer dissolved in an organic solvent makes it possible to obtain a lactam content in the coated particle of less than 0.5% by weight relative to the weight of gabapentin or of pregabalin. In addition, the polymer coating also makes it possible to mask the taste of the xcex3-aminobutyric acid analogue without, however, delaying its release, thus making it possible to obtain usual concentrations in the plasma.
To obtain the masking of the taste while at the same time allowing the rapid release of the gabapentin, the polymer represents between 60 and 80% by weight of the gabapentin.
For a polymer proportion of less than 60%, sufficient masking of the taste is not obtained. Conversely, for a polymer proportion of greater than 80%, the gabapentin taste is entirely masked, but the active principle may not be released quickly enough.
Advantageously, the gabapentin particles are coated to a proportion of 70% by weight of polymer.
Similarly, as regards pregabalin, to obtain masking of the taste while at the same time allowing rapid release of the molecule, the polymer represents between 15 and 30% by weight of the pregabalin.
For a polymer proportion of less than 15%, sufficient masking of the taste is not obtained. Conversely, for a polymer proportion of greater than 35%, the gabapentin taste is entirely masked, but the active principle may not be released quickly enough.
Advantageously, the pregabalin particles are coated to a proportion of 20% by weight of polymer.
Moreover, the various processes for manufacturing gabapentin or pregabalin give particles which can range between 2 micrometers and a few millimeters in size.
If the size of the particles of active principle analogue is too small, i.e. about 50 micrometers, spraying of the solution leads to non-uniform coating of the particles.
To solve this problem, it is sought to increase the size of the particles by spraying a solution of a water-soluble binder in an organic solvent on to the said particles by the so-called fluidized air bed technique, also known as xe2x80x9cspray coatingxe2x80x9d, after which the aggregated particles obtained are screened and calibrated.
The actual coating of the gabapentin or pregabalin is carried out on the aggregated or non-aggregated particles, the size of which is between 100 and 400 micrometers, preferably in the region of 250 micrometers, by the same so-called fluidized bed technique.
The coated gabapentin or pregabalin particle obtained is in the form of a coated, aggregated or non-aggregated particle, the size of which is between 100 and 450 micrometers, with a median of about 250 micrometers.
To dissolve the polymer, the organic solvent is chosen from the group comprising acetone, ethanol and isopropanol, alone or as a mixture.
According to one advantageous embodiment, the polymer is dissolved in a solvent comprising 50 parts of acetone and 50 parts of ethanol per 100 parts on a mass/mass basis.
Similarly, when a step of pre-uniforming of the size of the gabapentin or pregabalin particles is carried out, the binder is dissolved in an organic solvent which is identical to or different from the one used in the spraying operation.
Moreover, to obtain a polymer coating which both allows the xcex3-aminobutyric acid analogue to be released rapidly and allows the taste of the active molecule to be masked, the polymer is chosen from the group comprising polymethacrylate, aminoethyl methacrylate copolymers and cellulose polymers, alone or as a mixture.
Advantageously, the polymethacrylate is a Eudragit, in particular Eudragit E(copyright) sold by the company Rxc3x6hm.
Among the cellulose polymers which can be chosen are ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and cellulose acetophthalate, alone or as a mixture. Moreover, it may be necessary to combine plasticizers such as ethyl phthalate with the said polymer.
To optimize the masking of the taste of the active principle, the coating solution can also contain a sweetener chosen from the group comprising aspartam, potassium acesulfam, sodium saccharinate, monoammonium glycyrrhizinate, sugars and derivatives, as well as polyols and derivatives, alone or as a mixture.
In practice, the sweetener represents between 1 and 6% by weight of the xcex3-aminobutyric acid analogue.
Moreover, to avoid electrostatic phenomena during the coating operation and thereby allow better control of the process, the solution also comprises an antistatic agent chosen from the group comprising colloidal silica, precipitated silica and talc.
In practice, the antistatic agent represents between 2 and 8% by weight of the xcex3-aminobutyric acid analogue, advantageously between 5 and 6% by weight.
According to another characteristic of the process of the invention, the spraying both of the dissolved polymer and of the dissolved binder is carried out as already stated by the fluidized bed technique.
On the laboratory scale, the spraying-air inlet temperature should be minimal and more particularly between 35 and 45xc2x0 C., advantageously 40xc2x0 C.
On the industrial scale, the spraying-air inlet temperature is higher and is more particularly between 40 and 80xc2x0 C., advantageously 60xc2x0 C.
Be that as it may, and in both cases, the temperature of the aggregated or non-aggregated particles during the coating operation should be minimal and advantageously between 20 and 30xc2x0 C.
The coated gabapentin or pregabalin particles obtained can be used in any adequate pharmaceutical form, it being understood that the lactam content of the said pharmaceutical form is less than 0.5% by weight relative to the weight of GABA analogue.
In a first embodiment, the coated particles are used in their native form, in the form of a sachet.
According to one advantageous embodiment of the invention, the coated particles can be subjected to a tabletting step after the said coated particles have been dry-premixed with the usual tabletting excipients.
The excipients used for the manufacture of these tablets are known to those skilled in the art and are chosen in particular from the group comprising diluents, lubricants, flavourings and sweeteners, alone or as a mixture.
The tablets which can be obtained according to the process of the invention may advantageously be of two types.
The first type corresponds to multiparticulate tablets which break down quickly without water being supplied, in less than 60 seconds in the oral cavity, these tablets also being known as Flashtab(copyright), which is a trademark registered by the Applicant, and are described more particularly in document EP-A-548,356.
In this case, the excipients added during the tabletting step also comprise at least one disintegrating agent capable of allowing rapid crumbling of the active principle.
Advantageously, the disintegrating agent is chosen from the group comprising sodium carboxymethylcellulose, crosslinked PVP (also known as cross-povidone) and carboxymethyl starch.
Moreover, the polymer intended for coating the gabapentin or pregabalin particles must be chosen such that it is insoluble at neutral pH, corresponding to the pH of the saliva (thus masking the taste) and such that it is soluble or permeable at a pH of between 1 and 4 corresponding to the gastric pH.
Furthermore, the hardness of the tablet is between 30 and 70 N, advantageously 50 N.
The second type of tablet corresponds to so-called xe2x80x9cfast-dispersiblexe2x80x9d tablets, i.e. tablets which are rapidly dispersible in water, which can be broken down in a very short time  less than 1 minute, preferably  less than 15 seconds, in a minimum volume of water which will depend on the mass of the tablet.
The latter pharmaceutical form can thus advantageously be used in paediatrics.
In this case, the excipients added during the tabletting operation will also comprise not only a crumbling agent but also an agent for maintaining the coated particles in suspension or a swelling agent.
Furthermore, the hardness of the tablet obtained is between 30 and 100 N, advantageously 70 N.